As recognized in the RFA for this supplement, pulmonary hypertension (PH) is a major cause of morbidity and mortality in children with Down syndrome (DS), yet mechanisms underlying the high risk for PH in DS and clinical approaches to identify at risk subjects to optimize strategies for their evaluation and care remain incompletely understood. Although susceptibility for the development of pulmonary vascular disease is much greater in newborns, infants and children with DS than non-DS subjects, the exact incidence, nature of disease, longitudinal course and clinical outcomes are uncertain. DS newborns are at greater risk for persistent pulmonary hypertension of the newborn at birth and are at greater risk for a more protracted course of PH after NICU discharge. Children with DS and congenital heart disease have more severe PH than non-DS children with similar lesions. In addition, DS subjects also frequently develop PH during childhood that are associated with respiratory co-morbidities such as laryngomalacia, tracheomalacia, aspiration, sleep apnea and other causes of lung disease. Thus, PH impacts the quality of life, activity and survival in DS, but longitudinal studies that assess the clinical course, associated cardiorespiratory problems and outcomes are currently lacking. With support from the NHLBI, we have been established a U01 program grant to develop a sustainable, open source registry that includes the fusion of data from traditional approaches with informatics strategies data obtain from electronic health records (EHR) in order to advance research in pediatric pulmonary vascular disease (U01 HL12118; S Abman and K Mandl, co-PIs). More specifically, this grant includes the Children?s Hospital Informatics Program at Harvard University, led by Dr. Ken Mandl, as well as investigators from 8 academic medical centers that constitute the Pediatric Pulmonary Hypertension Network (PPHNet). The PPHNet is a collaborative, multi-institution group of sites from throughout North America that have strong and successful inter-disciplinary programs in pediatric PH. During the past 4 years of funding, this grant program has successfully exceeded planned patient enrollment milestones with over 1500 children with PH, and we are now in the no cost extension period for data analysis and completion of manuscripts. In response to this RFA, we now propose to use our PPHNet database to extensively phenotype and characterize the natural history and diversity of factors that contribute to high risk for PH in DS subjects, to define co-morbidities and the impact of respiratory and PH drug interventions that modulate disease outcomes. This project will extend ongoing work from our current U01 on pediatric PH that has led to the development of strong infrastructure for this project, including high participation of PIs and sites from PPHNet, the development of a biorepository and the ability to perform data fusion through informatics strategies that link registry with EHR datasets. In addition to being highly responsive to the recognized importance and need for studies of PH in DS, this current proposal for a supplement to study PH in children with DS is clearly within the scope of the parent award and is not specifically focused on DS. Ongoing aims of the parent grant were to establish the PPHNet Registry, develop informatic strategies to successfully pull relevant clinical data from electronic health records, and then to compare datasets and enhance discoveries through fusion of these datasets. Although this parent grant has supported the development of infrastructure for extensive studies of pediatric PH, the current grant funding does not include comprehensive studies of children with DS. Therefore, in this proposal, we hypothesize that neonates, infants and children with DS are at high risk for the development of PH, that DS children have distinct clinical courses and responses to therapy in comparison with subjects with other diseases associated with PH in the absence of DS, and that comprehensive phenotyping of subjects with DS will enhance clinical strategies for successful interventions. More specifically, the purpose of this proposal is to achieve several goals, including:incorporating subjects with DS into our existing disease cohorts of pediatric PH; developing a comprehensive characterization of PH phenotypes and disease-modifying risk factors in children with DS; and to identify approaches to optimize the evaluation and care of PH in DS subjects. We further seek to collect biospecimens for whole exome sequencing and proteomic studies to provide pilot data to identify novel genetic factors and biomarkers that modulate outcomes and may help to identify factors that make individuals with DS susceptible or protected from severe PH by comparing samples from DS subjects with and without PH.